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Mutual regulation between deubiquitinase CYLD and retroviral oncoprotein Tax

Xuefeng Wu1,2, Minying Zhang3,2, Shao-Cong Sun2

  • 1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.

Cell & Bioscience
|August 10, 2011
PubMed
Abstract

Insights

The deubiquitinase CYLD inhibits human T-cell leukemia virus type 1 (HTLV1) oncoprotein Tax ubiquitination and NF-κB activation. HTLV1 overrides this by phosphorylating CYLD, promoting T-cell transformation.

Area of Science:

  • Virology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Human T-cell leukemia virus type 1 (HTLV1) oncoprotein Tax drives T-cell transformation by activating NF-κB.
  • Tax signaling requires ubiquitination, but its regulation is not fully understood.

Purpose of the Study:

  • To investigate the role of the deubiquitinase CYLD in regulating Tax ubiquitination and signaling.
  • To elucidate the mechanism by which HTLV1 overcomes CYLD's inhibitory function.

Main Methods:

  • Co-immunoprecipitation to assess physical interaction between CYLD and Tax.
  • Analysis of ubiquitination status of Tax.
  • Assessment of NF-κB pathway activation (IKK and Tak1).
  • Phosphorylation studies of CYLD in HTLV1-transformed cells.

Main Results:

  • CYLD physically interacts with Tax and inhibits its ubiquitination.
  • CYLD inhibits Tax-mediated IKK activation but not Tak1 activation.
  • CYLD is constitutively phosphorylated in HTLV1-transformed cells, inactivating its function.
  • A phospho-mimetic CYLD mutant cannot inhibit Tax ubiquitination.

Conclusions:

  • CYLD negatively regulates Tax signaling by inhibiting Tax ubiquitination.
  • HTLV1 likely induces CYLD phosphorylation to overcome its inhibitory effect, ensuring persistent NF-κB activation and T-cell transformation.

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